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Radical hysterectomy is not associated with a survival benefit for patients with stage II endometrial carcinoma
YGYNO-977836; No. of pages: 5; 4C: Gynecologic Oncology xxx (xxxx) xxx
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Radical hysterectomy is not associated with a survival benefit for patients with stage II endometrial carcinoma Dimitrios Nasioudis ⁎, Sruthi Sakamuri, Emily M. Ko, Ashley F. Haggerty, Robert L. Giuntoli II, Robert A. Burger, Mark A. Morgan, Nawar A. Latif Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA
H I G H L I G H T S • Rate of radical hysterectomy for patients with stage II endometrial cancer was 10.5%. • Patients who underwent radical hysterectomy had longer hospital stay and higher 90-day mortality. • Radical hysterectomy did not confer a survival benefit in this cohort.
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Article history: Received 4 November 2019 Received in revised form 1 February 2020 Accepted 2 February 2020 Available online xxxx Keywords: Uterus Endometrial cancer Hysterectomy Stage II
a b s t r a c t Objective. To evaluate the role of radical hysterectomy in the management of patients with stage II endometrial carcinoma. Materials. Patients diagnosed between 2004 and 2015, with stage II (based on the revised FIGO staging) endometrial carcinoma who had hysterectomy and regional lymph node surgery were identified in the National Cancer Database. Those who had radical or modified radical (RH), or total hysterectomy (TH) were selected. Overall survival (OS) was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. Results. A total of 7552 patients who met the inclusion criteria were identified. Rate of RH was 10.5%. Those who underwent RH had longer hospital stay (median 3 vs 2 days, p b 0.001) and a higher 90-day (1.6% vs 0.8%, p = 0.05) mortality. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955) (p = 0.62); 5-year survival rates were 77.4% and 76.9%, respectively. After controlling for patient age (b65, ≥65 years), race (white, black, other/unknown), insurance status, presence of comorbidities, tumor size (b5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21). Conclusions. Radical hysterectomy was not associated with a survival benefit in a cohort of patients with stage II endometrial carcinoma. © 2020 Elsevier Inc. All rights reserved.
1. Introduction Endometrial cancer is the most prevalent gynecologic malignancy in the United States with approximately 62,000 estimated new cases diagnosed in 2019 [1]. Based on the current FIGO staging schema patients with tumors that invade the cervical stroma and do not extend beyond the uterus are classified as stage II [2]. Patients rarely present with stage
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 1 West Gates, Philadelphia, PA 19104, USA. E-mail address: [email protected] (D. Nasioudis).
II disease, thus the optimal management of these patients is not wellestablished especially given the difficulty to discriminate between cervical involvement from an endometrial cancer and a primary cervical malignancy [3]. Given the concern for possible invasion of the parametrial tissues, historically these patients underwent radical hysterectomy [4]. Based on the NCCN guidelines an alternative approach is simple hysterectomy followed by adjuvant radiation therapy [5]. Several retrospective studies have failed to demonstrate superior oncologic outcomes for radical hysterectomy that can be associated with significant morbidity [4,6]. Given the paucity of evidence the aim of the present study was to evaluate the prevalence and outcomes of radical hysterectomy for patients with FIGO stage II endometrial cancer using a large multi-institutional database.
https://doi.org/10.1016/j.ygyno.2020.02.003 0090-8258/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
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D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
2. Materials and methods In the present study a cohort of patients diagnosed between 2004 and 2015 with an invasive tumor of the uterus was selected from the National Cancer Data Base (NCDB). The NCDB, established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons, is a hospital-based database capturing approximately 70% of all malignancies diagnosed in the United States. Patient data are prospectively collected from participating commission-accredited cancer programs and are frequently audited. All data are de-identified and available for research purposes. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data [7]. The present study was deemed exempt from Institutional Board Review from Penn Medicine. Based on ICD-O-3 histology codes patients diagnosed with a pathologically confirmed endometrioid (8380–8383), serous (8441, 8460, 8461), clear cell (8310), and carcinosarcoma (8950, 8951, 8980, 8981) without a history of a prior tumor were identified. Those with pathological stage IIB (if diagnosed between 2004 and 2009) or stage II disease (if diagnosed between 2010 and 2014) were selected for further analysis, while misclassified cases were excluded by evaluating the extent of disease, and the presence of metastasis from the variables of the collaborative staging schema. Similar to prior studies using large datasets, based on the site-specific surgery codes two groups were formed; patients who underwent simple/total hysterectomy (SH) and those who underwent radical, extended radical or modified radical hysterectomy (RH) [8,9]. Patients who had subtotal hysterectomy, or hysterectomy NOS (not otherwise specified), as well as those who received radiation therapy before surgery were excluded from the present study. In addition, given the relatively high prevalence of regional lymph node metastases we opted to exclude patients who did not undergo regional lymph node sampling/dissection to ensure adequate staging. Moreover, patients with positive regional lymph nodes per pathology report were excluded. Receipt of adjuvant chemotherapy and radiation therapy (vaginal brachytherapy and/or external beam radiation) was defined as treatment received within 6 months from surgery. Demographic, clinical-pathological, and treatment variables were extracted from the de-identified NCDB dataset. For analysis purposes, patient race was recoded into White, Black and Other/Unknown, insurance status into Private, Government (including Medicaid and Medicare) and Uninsured/Unknown. Based on prior studies age was grouped into b65 and ≥65 years to define an older population [10,11]. The presence of co-morbidities was assessed from the Charlson-Deyo Comorbidity index, a clinical comorbidity index designed for use with medical records that takes into account the severity of comorbid condition and classified as absent (score 0) or present (score ≥ 1). In the NCDB, the exact location of tumor is not recorded however tumor size reflects the largest diameter of primary tumor and is based on the pathology report but if not available it is base ped on the operative note and/or preoperative imaging. When available tumor size was categorized into b5 cm and ≥5 cm. Primary endpoint was overall survival (OS) defined as the months elapsed from tumor diagnosis to the date of death or last follow up. Secondary outcomes were 30 and 90-day mortality, median hospital stay and rate of unplanned 30-day readmission. The frequency of distribution of categorical variables was compared with the chi-square test or Fisher's exact test and continuous variables with the Mann Whitney U test. Kaplan-Meier curves were generated to determine 5-year OS rates while univariate analysis was performed with the log-rank test. A Cox multivariate analysis factors to control for associated with overall survival by univariate analysis. Patients who received chemotherapy or radiation therapy with unknown interval from primary the surgery were excluded from the multivariate model. A planned stratified analysis by type of hysterectomy and receipt
of radiation therapy was performed. Survival data were available for patients diagnosed between 2004 and 2014. In a sensitivity analysis, patients with clinical stage II disease (IIB if diagnosed between 2004 and 2009 and II if diagnosed between 2010 and 2015), without a history of another tumor, who did not receive radiation therapy before surgery and had lymphadenectomy and known type of hysterectomy were identified and their survival was evaluated based on the type of hysterectomy performed. All statistical analyses were performed with the SPSS v.24 statistical package (IBM Corp. Armonk, NY) and the alpha level of statistical significance was set at 0.05. 3. Results A total of 7552 patients who met the inclusion criteria were identified. Median patient age was 63 years (range 22–90), while the majority were White (82.6%), with government issued insurance (48.6%) and did not have any comorbidities (74.5%). The most common histologic subtype was endometrioid carcinoma (78.7%), followed by serous carcinoma (10.1%), carcinosarcoma (7.9%) and clear cell carcinoma (3.3%). Based on site-specific surgery codes, in the present cohort, 802 (10.5%) and 6750 (87.5%) patients underwent RH and SH, respectively. Among the 802 patients included in the RH group, 349 (43.5%) had a modified radical or extended hysterectomy, 220 (27.4%) had a radical hysterectomy/Wertheim procedure, 20 (2.5%) had an extended radical hysterectomy, and 213 (26.6%) had a modified radical/radical/extended radical hysterectomy NOS. Radiation therapy was administered to 5240 patients; 1153 (22%) received external beam radiation therapy (EBRT), 2169 (41.4%) received vaginal brachytherapy (VBT), 36 patients radiation therapy NOS while 1882 (35.9%) received combination of EBRT and VBT. Patients who underwent RH were younger (median age 61 vs 63 years, p b 0.001), had larger tumors (median 5.4 vs 5 cm, p b 0.001), were more likely to be managed in non-academic facilities (61.1% vs 55.9%, p = 0.007) and received more adjuvant chemotherapy (23.8% vs 19.5%, p = 0.004) compared to those who had SH. Moreover, they were less likely to have government-issued insurance (45% vs 49%, p b 0.001) and receive adjuvant radiation therapy (58.6% vs 68.5%, p b 0.001). Among patients who received radiation therapy, rates of EBRT (22.4% vs 20.2%), VBT (41.6% vs 42.2%) and EBRT + VBT (36% vs 37.7%) were comparable between patients who underwent SH and RH, p = 0.52. The two groups were comparable in terms of histology (p = 0.41), race (p = 0.93), median income (p = 0.50), and the presence of comorbidities (p = 0.84), Patients who had RH were more likely to have at least 10 lymph nodes removed compared to those who had SH (74.2% vs 65.5%, p b 0.001). Data on the performance of para-aortic LND were available for 4705 patients, with a higher rate noted for those who had RH (66.5% vs 54.2%, p b 0.001). Information on the status of surgical margins was available for 7059 patients; the rate of positive margins was slightly higher in the RH group (3.6% vs 2.2%, p = 0.02). Table 1 summarizes the clinical-pathological characteristics of patient population stratified by type of hysterectomy. Unplanned 30-day readmission rate was comparable between patients who had RH (4.2%) and TH (3.1%), p = 0.09. However, those who underwent RH had longer hospital stay (median 3 vs 2 days, p b 0.001). Rates of 30-day mortality (0.6% vs 0.4%, p = 0.52) were comparable but patients who had RH had a trend towards higher 90-day mortality (1.6% vs 0.8%, p = 0.05). There was no difference in unplanned 30-day readmission rates (3.8% vs 4.2%, p = 0.80), median hospital stay (median 3 days, p = 0.05), and 90-day mortality (1.7% vs 1.4%, p = 0.79) between patients who had modified radical and radical/extended radical hysterectomy. The median follow-up in RH and SH groups was 60.94 and 60.68 months, respectively. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955), p = 0.62 from
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx Table 1 Characteristics of patients with FIGO stage II endometrial cancer stratified by type of hysterectomy; RH: radical, SH: simple hysterectomy. SH Age (years) b65 ≥65 Race White Black Other/unknown Median income ($) b38,000 38,000–47,999 48,000–62,999 ≥63,000 Comorbidities No Yes Insurance Private Government Uninsured/Unk Reporting facility Academic Non-academic Histology Endometrioid Non-endometrioid LVSI No Yes Size b5 cm ≥5 cm LN number removed b10 ≥10 Para-aortic LND No Yes Adjuvant radiotherapy No Yes Adjuvant chemotherapy No Yes
RH
p value b0.001
3683 (54.6%) 3067 (45.4%)
500 (62.3%) 302 (37.7%) 0.93
5580 (82.7%) 788 (11.7%) 382 (5.7%)
660 (82.3%) 94 (11.7%) 48 (6%)
1198 (17.9%) 1551 (23.2%) 1833 (27.4%) 2105 (31.5%)
158 (19.9%) 182 (22.9%) 219 (27.6%) 235 (29.6%)
5027 (74.5%) 1723 (25.5%)
600 (74.8%) 202 (25.2%)
3168 (46.9%) 3308 (49%) 274 (4.1%)
380 (47.4%) 361 (45%) 61 (7.6%)
2914 (44.1%) 3700 (55.9%)
301 (38.9%) 472 (61.1%)
5321 (78.8%) 1429 (21.2%)
622 (77.6%) 180 (22.4%)
2561 (65.5%) 1349 (34.5%)
284 (65%) 153 (35%)
2622 (49.7%) 2650 (50.3%)
278 (42.4%) 377 (57.6%)
2282 (34.5%) 4327 (65.5%)
203 (25.8%) 583 (74.2%)
0.50
0.84
b0.001
0.007
0.41
0.83
b0.001
b0.001
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Table 2 Results of multivariate survival analysis. Hazard ratio (95% confidence interval) Type of hysterectomy Simple Radical Age (years) b65 ≥65 Race White Black Other/unknown Comorbidities No Yes Insurance Private Government Uninsured/Unk Histology Endometrioid Non-endometrioid Size b5 cm ≥5 cm Unknown LN number removed b10 ≥10 Adjuvant radiotherapy No Yes Adjuvant chemotherapy No Yes
p value 0.89
Ref 1.01 (0.85, 1.21) b0.001 Ref 2.06 (1.78, 2.40) b0.001 Ref 1.38 (1.20, 1.60) 0.93 (0.71, 1.21) 0.005 Ref 1.18 (1.05, 1.32) b0.001 Ref 1.38 (1.18, 1.60) 1.14 (0.83, 1.57) b0.001 Ref 2.32 (2.04, 2.65) b0.001 Ref 1.44 (1.27, 1.63) 1.28 (1.11, 1.47) b0.001 Ref 0.77 (0.69, 0.86) b0.001 Ref 0.69 (0.62, 0.77) 0.001 Ref 0.78 (0.67, 0.91)
LN: lymph node. b0.001
1928 (45.8%) 2281 (54.2%)
166 (33.5%) 330 (66.5%)
2000 (31.5%) 4343 (68.5%)
312 (41.4%) 441 (58.6%)
5324 (80.5%) 1286 (19.5%)
600 (76.2%) 187 (23.8%)
b0.001
0.004
Missing values: para-aortic LND 4955 cases, number of LN removed 157 cases, adjuvant chemotherapy 155 cases, adjuvant radiation therapy 456 cases, type of facility 165 cases, LVSI 3205 cases, tumor size 1625 cases.
insurance status, presence of comorbidities, tumor size (b5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, the performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21) (Table 2). Among patients in the RH group, survival was comparable between those who had modified radical (n = 304) and radical/extended radical (n = 221) hysterectomy, p = 0.23; 5-yr OS rates were 75.7% and 80.3% respectively (Fig. 2). Patients who did not receive adjuvant RT (n = 2046) had worse OS than those who did (n = 4193), p b 0.001; 5-year OS were 69.8% and
log-rank; 5-year OS rates were 77.4% and 76.9% respectively (Fig. 1). Following stratification by tumor histology, there was no difference in OS between patients who had RH and SH, for endometrioid (p = 0.92) and non-endometrioid tumors (p = 0.41). After controlling for patient age (b65, ≥65 years), race (white, black, other/unknown),
Fig. 1. Overall survival of patients with stage II endometrial carcinoma stratified by type of hysterectomy. RH: radical hysterectomy, SH: simple hysterectomy.
Fig. 2. Overall survival of patients with stage II endometrial carcinoma who had radical and modified radical hysterectomy.
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
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D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
Fig. 3. Overall survival of patients with stage II endometrial carcinoma stratified by type of hysterectomy and receipt of adjuvant radiation therapy.
80.4% respectively. A stratified analysis by type of hysterectomy and receipt of radiation therapy was performed. Overall survival was better for patients undergoing simple (n = 3805) and radical (n = 388) hysterectomy with adjuvant RT compared to those who had radical (n = 277) and simple (n = 1769) hysterectomy without adjuvant RT, p b 0.001; 5-year OS rates were 80.4%, 79.9%, 73.8% and 69.1% respectively (Fig. 3). By multivariate analysis after controlling for patient age, race, insurance status, presence of comorbidities, tumor size, histology, performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy, patients who had SH with adjuvant RT had better survival compared to those who had RH without adjuvant RT (HR: 0.72, 95% CI: 0.56, 0.92). There was no difference in survival between patients who had RH with RT and those who had SH with RT (HR: 0.94, 95% CI: 0.73, 1.19). In a planned sensitivity analysis, 3902 patients with clinical stage II were identified. The rate of RH was 15.4% in that cohort. Patients who had SH (n = 2956) had similar OS compared to those who had RH (n = 552), p = 0.08; 5-year OS rates were 73.4% and 69.8%, respectively. After controlling for patient age, race, insurance status, presence of comorbidities, tumor size, histology, performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy patients who had radical hysterectomy without adjuvant RT (n = 245) had worse survival than those who had SH with adjuvant RT (n = 1519) (HR: 0.72, 95% CI: 0.56, 0.93). For patients with clinical stage II who had pathologically confirmed positive regional lymph nodes, those who underwent radical hysterectomy (n = 103) had worse survival compared to those who had SH (n = 313), p = 0.013; 5-yr OS rates were 42.1% and 55.5% respectively.
4. Discussion We examined a large cohort of patients with FIGO (2009) stage II endometrial carcinoma and we did not observe an overall survival benefit for patients who underwent radical hysterectomy even after controlling for multiple confounders including tumor histology and receipt of adjuvant radiation therapy. On the other hand, RH was associated with longer inpatient stay and a higher 90-day mortality rate. Interestingly, in a stratified analysis, patients receiving RH without adjuvant radiation therapy had worse survival than those who had SH with adjuvant radiation therapy, even after controlling for confounders. We also performed a sensitivity analysis by examining patients with clinical stage II and demonstrated a lack of survival benefit for those undergoing
RH. Again, patients who underwent RH only had a worse survival compared to those undergoing SH with RT. The present results are consistent with those from prior retrospective studies. Recently, Liu et al. performed a systematic review of literature and meta-analysis and identified 10 retrospective studies with 2866 patients comparing the oncologic outcomes of those with stage II endometrial cancer by type of hysterectomy [4]. Based on 9 studies, RH was not associated with an overall survival benefit (HR: 0.92, 95% CI: 0.72, 1.16). Similarly, based on three studies, there was no difference in progression free survival (HR: 0.75, 95% CI: 0.39, 1.42) between the two groups [4]. However, it should be noted that studies using the old FIGO 1988 schema were included in the meta-analysis. In an interesting study, Hasegawa et al. performed a multi-institutional retrospective study, and compared the rates of local relapse among 1355 patients with stage I–III endometrial cancer by type of hysterectomy; 26.4% underwent RH while none received radiation therapy as such local relapse rate reflected surgical control [12]. Disease recurrence developed in 116 (11.8%) patients in the SH group and in 47 (13.3%) patients in the RH group. Local recurrence was found in 53 (36.3%) in the SH group and in 19 (31.6%) sites in the RH group, while based on KaplanMeier method no significant difference was observed in the rates of local recurrence between the SH and RH groups, p = 0.93 [8]. To date only older studies that include patients with stage IIA disease, have demonstrated superior outcomes for patients undergoing RH. Sartori et al. found a 94% OS rate for 68 patients undergoing RH compared to 79% for 135 patients undergoing simple hysterectomy [13]. Similar to our study, Cohn et al. examined the survival of 162 comprehensively staged pathological stage II patients managed in 6 academic institutions, 25% underwent radical hysterectomy with an improved disease free survival (94% vs 76%, p = 0.05) after a median follow-up of 26 months [14]. Two prior population-based studies have investigated the role of radical hysterectomy for patients with stage II endometrial cancer. Similar to our study, Wright et al. examined the Surveillance Epidemiology and End Results (SEER) database and identified 1577 patients with pathologic stage II disease [8]. Authors reported a rate of radical hysterectomy of 24% however RH had no effect on survival (HR: 0.86; 95% CI: 0.61–1.23) [10]. A limitation of that study was the inclusion of patients with endocervical gland involvement only (n = 495) currently assigned to stage I disease according to the revised endometrial cancer staging schema [8]. In another study using the SEER database, Koskas et al. performed a 2:1 matching analysis and compared the oncologic outcomes of 273 patients with type 1 endometrial cancer who underwent a radical hysterectomy for pathological stage II endometrial cancer with 546 patients who received a simple hysterectomy [9]. The 3-year cancerrelated survivals in the radical and simple hysterectomy groups were 88.7% and 94.1%, respectively. After adjusting for radiation therapy administration, there was no difference between the two groups in terms of cancer-related survival or overall survival [9]. A major strength of the present study is the large number of surgically staged patients identified. Moreover, we were able to control for multiple confounders and perform stratified analyses, as well as a sensitivity analysis that included patients with clinical stage II disease. However, several limitations should be noted. Firstly, surgical codes as provided by the NCDB were used to identify patients who had simple, modified radical and radical hysterectomy. As such we could not verify whether each individual surgeon used a classification system such as the Piver-Rutledge-Smith or Querleu-Morrow classification systems, while we could not perform quality control for each type of surgery. Given the absence of preoperative data a potential selection bias is pausible. Patients with more aggressive appearing tumors may have been more likely to undergo RH. Due to the lack of central pathology report, possible tumor misclassifications cannot be excluded. Information on patient related parameters that may have influenced surgeon choice towards RH or SH such as patient's surgical history, uterine size, and
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
specific comorbidities, were lacking. Similarly, indications and rationale of adjuvant chemotherapy and radiotherapy administration for each patient is not collected. We could not also verify whether patients who did not undergo para-aortic LND received radiation therapy to the paraaortic lymphatic beds. In addition, the NCDB does not collect information on cancer relapse or the cause of death, precluding us from analyzing differences in progression free and cause specific survival. Lastly, contrary to major randomized trials we found a survival benefit among patients who received radiation therapy. We could not verify whether this benefit is attributed to patient selection bias since functional status is not collected in the NCDB. The results of the present study do not support the routine use of radical hysterectomy for stage II endometrial cancer. A possible future international randomized trial may clarify the surgical management for patients with stage II endometrial cancer, though technically challenging. Contributions DN: conception, statistical analysis, critical analysis, and drafting/ final editing. SS: critical analysis and drafting/final editing. EK: critical analysis and drafting/final editing. AH: critical analysis and drafting/final editing. RG: critical analysis and drafting/final editing. RB: critical analysis and drafting/final editing. MM: critical analysis and drafting, final editing. NA: supervision, critical analysis and drafting/final editing. Declaration of competing interest No conflicts of interest to report.
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Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Radical hysterectomy is not associated with a survival benefit for patients with stage II endometrial carcinoma Dimitrios Nasioudis ⁎, Sruthi Sakamuri, Emily M. Ko, Ashley F. Haggerty, Robert L. Giuntoli II, Robert A. Burger, Mark A. Morgan, Nawar A. Latif Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA
H I G H L I G H T S • Rate of radical hysterectomy for patients with stage II endometrial cancer was 10.5%. • Patients who underwent radical hysterectomy had longer hospital stay and higher 90-day mortality. • Radical hysterectomy did not confer a survival benefit in this cohort.
a r t i c l e
i n f o
Article history: Received 4 November 2019 Received in revised form 1 February 2020 Accepted 2 February 2020 Available online xxxx Keywords: Uterus Endometrial cancer Hysterectomy Stage II
a b s t r a c t Objective. To evaluate the role of radical hysterectomy in the management of patients with stage II endometrial carcinoma. Materials. Patients diagnosed between 2004 and 2015, with stage II (based on the revised FIGO staging) endometrial carcinoma who had hysterectomy and regional lymph node surgery were identified in the National Cancer Database. Those who had radical or modified radical (RH), or total hysterectomy (TH) were selected. Overall survival (OS) was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. Results. A total of 7552 patients who met the inclusion criteria were identified. Rate of RH was 10.5%. Those who underwent RH had longer hospital stay (median 3 vs 2 days, p b 0.001) and a higher 90-day (1.6% vs 0.8%, p = 0.05) mortality. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955) (p = 0.62); 5-year survival rates were 77.4% and 76.9%, respectively. After controlling for patient age (b65, ≥65 years), race (white, black, other/unknown), insurance status, presence of comorbidities, tumor size (b5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21). Conclusions. Radical hysterectomy was not associated with a survival benefit in a cohort of patients with stage II endometrial carcinoma. © 2020 Elsevier Inc. All rights reserved.
1. Introduction Endometrial cancer is the most prevalent gynecologic malignancy in the United States with approximately 62,000 estimated new cases diagnosed in 2019 [1]. Based on the current FIGO staging schema patients with tumors that invade the cervical stroma and do not extend beyond the uterus are classified as stage II [2]. Patients rarely present with stage
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 1 West Gates, Philadelphia, PA 19104, USA. E-mail address: [email protected] (D. Nasioudis).
II disease, thus the optimal management of these patients is not wellestablished especially given the difficulty to discriminate between cervical involvement from an endometrial cancer and a primary cervical malignancy [3]. Given the concern for possible invasion of the parametrial tissues, historically these patients underwent radical hysterectomy [4]. Based on the NCCN guidelines an alternative approach is simple hysterectomy followed by adjuvant radiation therapy [5]. Several retrospective studies have failed to demonstrate superior oncologic outcomes for radical hysterectomy that can be associated with significant morbidity [4,6]. Given the paucity of evidence the aim of the present study was to evaluate the prevalence and outcomes of radical hysterectomy for patients with FIGO stage II endometrial cancer using a large multi-institutional database.
https://doi.org/10.1016/j.ygyno.2020.02.003 0090-8258/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
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D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
2. Materials and methods In the present study a cohort of patients diagnosed between 2004 and 2015 with an invasive tumor of the uterus was selected from the National Cancer Data Base (NCDB). The NCDB, established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons, is a hospital-based database capturing approximately 70% of all malignancies diagnosed in the United States. Patient data are prospectively collected from participating commission-accredited cancer programs and are frequently audited. All data are de-identified and available for research purposes. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data [7]. The present study was deemed exempt from Institutional Board Review from Penn Medicine. Based on ICD-O-3 histology codes patients diagnosed with a pathologically confirmed endometrioid (8380–8383), serous (8441, 8460, 8461), clear cell (8310), and carcinosarcoma (8950, 8951, 8980, 8981) without a history of a prior tumor were identified. Those with pathological stage IIB (if diagnosed between 2004 and 2009) or stage II disease (if diagnosed between 2010 and 2014) were selected for further analysis, while misclassified cases were excluded by evaluating the extent of disease, and the presence of metastasis from the variables of the collaborative staging schema. Similar to prior studies using large datasets, based on the site-specific surgery codes two groups were formed; patients who underwent simple/total hysterectomy (SH) and those who underwent radical, extended radical or modified radical hysterectomy (RH) [8,9]. Patients who had subtotal hysterectomy, or hysterectomy NOS (not otherwise specified), as well as those who received radiation therapy before surgery were excluded from the present study. In addition, given the relatively high prevalence of regional lymph node metastases we opted to exclude patients who did not undergo regional lymph node sampling/dissection to ensure adequate staging. Moreover, patients with positive regional lymph nodes per pathology report were excluded. Receipt of adjuvant chemotherapy and radiation therapy (vaginal brachytherapy and/or external beam radiation) was defined as treatment received within 6 months from surgery. Demographic, clinical-pathological, and treatment variables were extracted from the de-identified NCDB dataset. For analysis purposes, patient race was recoded into White, Black and Other/Unknown, insurance status into Private, Government (including Medicaid and Medicare) and Uninsured/Unknown. Based on prior studies age was grouped into b65 and ≥65 years to define an older population [10,11]. The presence of co-morbidities was assessed from the Charlson-Deyo Comorbidity index, a clinical comorbidity index designed for use with medical records that takes into account the severity of comorbid condition and classified as absent (score 0) or present (score ≥ 1). In the NCDB, the exact location of tumor is not recorded however tumor size reflects the largest diameter of primary tumor and is based on the pathology report but if not available it is base ped on the operative note and/or preoperative imaging. When available tumor size was categorized into b5 cm and ≥5 cm. Primary endpoint was overall survival (OS) defined as the months elapsed from tumor diagnosis to the date of death or last follow up. Secondary outcomes were 30 and 90-day mortality, median hospital stay and rate of unplanned 30-day readmission. The frequency of distribution of categorical variables was compared with the chi-square test or Fisher's exact test and continuous variables with the Mann Whitney U test. Kaplan-Meier curves were generated to determine 5-year OS rates while univariate analysis was performed with the log-rank test. A Cox multivariate analysis factors to control for associated with overall survival by univariate analysis. Patients who received chemotherapy or radiation therapy with unknown interval from primary the surgery were excluded from the multivariate model. A planned stratified analysis by type of hysterectomy and receipt
of radiation therapy was performed. Survival data were available for patients diagnosed between 2004 and 2014. In a sensitivity analysis, patients with clinical stage II disease (IIB if diagnosed between 2004 and 2009 and II if diagnosed between 2010 and 2015), without a history of another tumor, who did not receive radiation therapy before surgery and had lymphadenectomy and known type of hysterectomy were identified and their survival was evaluated based on the type of hysterectomy performed. All statistical analyses were performed with the SPSS v.24 statistical package (IBM Corp. Armonk, NY) and the alpha level of statistical significance was set at 0.05. 3. Results A total of 7552 patients who met the inclusion criteria were identified. Median patient age was 63 years (range 22–90), while the majority were White (82.6%), with government issued insurance (48.6%) and did not have any comorbidities (74.5%). The most common histologic subtype was endometrioid carcinoma (78.7%), followed by serous carcinoma (10.1%), carcinosarcoma (7.9%) and clear cell carcinoma (3.3%). Based on site-specific surgery codes, in the present cohort, 802 (10.5%) and 6750 (87.5%) patients underwent RH and SH, respectively. Among the 802 patients included in the RH group, 349 (43.5%) had a modified radical or extended hysterectomy, 220 (27.4%) had a radical hysterectomy/Wertheim procedure, 20 (2.5%) had an extended radical hysterectomy, and 213 (26.6%) had a modified radical/radical/extended radical hysterectomy NOS. Radiation therapy was administered to 5240 patients; 1153 (22%) received external beam radiation therapy (EBRT), 2169 (41.4%) received vaginal brachytherapy (VBT), 36 patients radiation therapy NOS while 1882 (35.9%) received combination of EBRT and VBT. Patients who underwent RH were younger (median age 61 vs 63 years, p b 0.001), had larger tumors (median 5.4 vs 5 cm, p b 0.001), were more likely to be managed in non-academic facilities (61.1% vs 55.9%, p = 0.007) and received more adjuvant chemotherapy (23.8% vs 19.5%, p = 0.004) compared to those who had SH. Moreover, they were less likely to have government-issued insurance (45% vs 49%, p b 0.001) and receive adjuvant radiation therapy (58.6% vs 68.5%, p b 0.001). Among patients who received radiation therapy, rates of EBRT (22.4% vs 20.2%), VBT (41.6% vs 42.2%) and EBRT + VBT (36% vs 37.7%) were comparable between patients who underwent SH and RH, p = 0.52. The two groups were comparable in terms of histology (p = 0.41), race (p = 0.93), median income (p = 0.50), and the presence of comorbidities (p = 0.84), Patients who had RH were more likely to have at least 10 lymph nodes removed compared to those who had SH (74.2% vs 65.5%, p b 0.001). Data on the performance of para-aortic LND were available for 4705 patients, with a higher rate noted for those who had RH (66.5% vs 54.2%, p b 0.001). Information on the status of surgical margins was available for 7059 patients; the rate of positive margins was slightly higher in the RH group (3.6% vs 2.2%, p = 0.02). Table 1 summarizes the clinical-pathological characteristics of patient population stratified by type of hysterectomy. Unplanned 30-day readmission rate was comparable between patients who had RH (4.2%) and TH (3.1%), p = 0.09. However, those who underwent RH had longer hospital stay (median 3 vs 2 days, p b 0.001). Rates of 30-day mortality (0.6% vs 0.4%, p = 0.52) were comparable but patients who had RH had a trend towards higher 90-day mortality (1.6% vs 0.8%, p = 0.05). There was no difference in unplanned 30-day readmission rates (3.8% vs 4.2%, p = 0.80), median hospital stay (median 3 days, p = 0.05), and 90-day mortality (1.7% vs 1.4%, p = 0.79) between patients who had modified radical and radical/extended radical hysterectomy. The median follow-up in RH and SH groups was 60.94 and 60.68 months, respectively. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955), p = 0.62 from
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx Table 1 Characteristics of patients with FIGO stage II endometrial cancer stratified by type of hysterectomy; RH: radical, SH: simple hysterectomy. SH Age (years) b65 ≥65 Race White Black Other/unknown Median income ($) b38,000 38,000–47,999 48,000–62,999 ≥63,000 Comorbidities No Yes Insurance Private Government Uninsured/Unk Reporting facility Academic Non-academic Histology Endometrioid Non-endometrioid LVSI No Yes Size b5 cm ≥5 cm LN number removed b10 ≥10 Para-aortic LND No Yes Adjuvant radiotherapy No Yes Adjuvant chemotherapy No Yes
RH
p value b0.001
3683 (54.6%) 3067 (45.4%)
500 (62.3%) 302 (37.7%) 0.93
5580 (82.7%) 788 (11.7%) 382 (5.7%)
660 (82.3%) 94 (11.7%) 48 (6%)
1198 (17.9%) 1551 (23.2%) 1833 (27.4%) 2105 (31.5%)
158 (19.9%) 182 (22.9%) 219 (27.6%) 235 (29.6%)
5027 (74.5%) 1723 (25.5%)
600 (74.8%) 202 (25.2%)
3168 (46.9%) 3308 (49%) 274 (4.1%)
380 (47.4%) 361 (45%) 61 (7.6%)
2914 (44.1%) 3700 (55.9%)
301 (38.9%) 472 (61.1%)
5321 (78.8%) 1429 (21.2%)
622 (77.6%) 180 (22.4%)
2561 (65.5%) 1349 (34.5%)
284 (65%) 153 (35%)
2622 (49.7%) 2650 (50.3%)
278 (42.4%) 377 (57.6%)
2282 (34.5%) 4327 (65.5%)
203 (25.8%) 583 (74.2%)
0.50
0.84
b0.001
0.007
0.41
0.83
b0.001
b0.001
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Table 2 Results of multivariate survival analysis. Hazard ratio (95% confidence interval) Type of hysterectomy Simple Radical Age (years) b65 ≥65 Race White Black Other/unknown Comorbidities No Yes Insurance Private Government Uninsured/Unk Histology Endometrioid Non-endometrioid Size b5 cm ≥5 cm Unknown LN number removed b10 ≥10 Adjuvant radiotherapy No Yes Adjuvant chemotherapy No Yes
p value 0.89
Ref 1.01 (0.85, 1.21) b0.001 Ref 2.06 (1.78, 2.40) b0.001 Ref 1.38 (1.20, 1.60) 0.93 (0.71, 1.21) 0.005 Ref 1.18 (1.05, 1.32) b0.001 Ref 1.38 (1.18, 1.60) 1.14 (0.83, 1.57) b0.001 Ref 2.32 (2.04, 2.65) b0.001 Ref 1.44 (1.27, 1.63) 1.28 (1.11, 1.47) b0.001 Ref 0.77 (0.69, 0.86) b0.001 Ref 0.69 (0.62, 0.77) 0.001 Ref 0.78 (0.67, 0.91)
LN: lymph node. b0.001
1928 (45.8%) 2281 (54.2%)
166 (33.5%) 330 (66.5%)
2000 (31.5%) 4343 (68.5%)
312 (41.4%) 441 (58.6%)
5324 (80.5%) 1286 (19.5%)
600 (76.2%) 187 (23.8%)
b0.001
0.004
Missing values: para-aortic LND 4955 cases, number of LN removed 157 cases, adjuvant chemotherapy 155 cases, adjuvant radiation therapy 456 cases, type of facility 165 cases, LVSI 3205 cases, tumor size 1625 cases.
insurance status, presence of comorbidities, tumor size (b5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, the performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21) (Table 2). Among patients in the RH group, survival was comparable between those who had modified radical (n = 304) and radical/extended radical (n = 221) hysterectomy, p = 0.23; 5-yr OS rates were 75.7% and 80.3% respectively (Fig. 2). Patients who did not receive adjuvant RT (n = 2046) had worse OS than those who did (n = 4193), p b 0.001; 5-year OS were 69.8% and
log-rank; 5-year OS rates were 77.4% and 76.9% respectively (Fig. 1). Following stratification by tumor histology, there was no difference in OS between patients who had RH and SH, for endometrioid (p = 0.92) and non-endometrioid tumors (p = 0.41). After controlling for patient age (b65, ≥65 years), race (white, black, other/unknown),
Fig. 1. Overall survival of patients with stage II endometrial carcinoma stratified by type of hysterectomy. RH: radical hysterectomy, SH: simple hysterectomy.
Fig. 2. Overall survival of patients with stage II endometrial carcinoma who had radical and modified radical hysterectomy.
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
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D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
Fig. 3. Overall survival of patients with stage II endometrial carcinoma stratified by type of hysterectomy and receipt of adjuvant radiation therapy.
80.4% respectively. A stratified analysis by type of hysterectomy and receipt of radiation therapy was performed. Overall survival was better for patients undergoing simple (n = 3805) and radical (n = 388) hysterectomy with adjuvant RT compared to those who had radical (n = 277) and simple (n = 1769) hysterectomy without adjuvant RT, p b 0.001; 5-year OS rates were 80.4%, 79.9%, 73.8% and 69.1% respectively (Fig. 3). By multivariate analysis after controlling for patient age, race, insurance status, presence of comorbidities, tumor size, histology, performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy, patients who had SH with adjuvant RT had better survival compared to those who had RH without adjuvant RT (HR: 0.72, 95% CI: 0.56, 0.92). There was no difference in survival between patients who had RH with RT and those who had SH with RT (HR: 0.94, 95% CI: 0.73, 1.19). In a planned sensitivity analysis, 3902 patients with clinical stage II were identified. The rate of RH was 15.4% in that cohort. Patients who had SH (n = 2956) had similar OS compared to those who had RH (n = 552), p = 0.08; 5-year OS rates were 73.4% and 69.8%, respectively. After controlling for patient age, race, insurance status, presence of comorbidities, tumor size, histology, performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy patients who had radical hysterectomy without adjuvant RT (n = 245) had worse survival than those who had SH with adjuvant RT (n = 1519) (HR: 0.72, 95% CI: 0.56, 0.93). For patients with clinical stage II who had pathologically confirmed positive regional lymph nodes, those who underwent radical hysterectomy (n = 103) had worse survival compared to those who had SH (n = 313), p = 0.013; 5-yr OS rates were 42.1% and 55.5% respectively.
4. Discussion We examined a large cohort of patients with FIGO (2009) stage II endometrial carcinoma and we did not observe an overall survival benefit for patients who underwent radical hysterectomy even after controlling for multiple confounders including tumor histology and receipt of adjuvant radiation therapy. On the other hand, RH was associated with longer inpatient stay and a higher 90-day mortality rate. Interestingly, in a stratified analysis, patients receiving RH without adjuvant radiation therapy had worse survival than those who had SH with adjuvant radiation therapy, even after controlling for confounders. We also performed a sensitivity analysis by examining patients with clinical stage II and demonstrated a lack of survival benefit for those undergoing
RH. Again, patients who underwent RH only had a worse survival compared to those undergoing SH with RT. The present results are consistent with those from prior retrospective studies. Recently, Liu et al. performed a systematic review of literature and meta-analysis and identified 10 retrospective studies with 2866 patients comparing the oncologic outcomes of those with stage II endometrial cancer by type of hysterectomy [4]. Based on 9 studies, RH was not associated with an overall survival benefit (HR: 0.92, 95% CI: 0.72, 1.16). Similarly, based on three studies, there was no difference in progression free survival (HR: 0.75, 95% CI: 0.39, 1.42) between the two groups [4]. However, it should be noted that studies using the old FIGO 1988 schema were included in the meta-analysis. In an interesting study, Hasegawa et al. performed a multi-institutional retrospective study, and compared the rates of local relapse among 1355 patients with stage I–III endometrial cancer by type of hysterectomy; 26.4% underwent RH while none received radiation therapy as such local relapse rate reflected surgical control [12]. Disease recurrence developed in 116 (11.8%) patients in the SH group and in 47 (13.3%) patients in the RH group. Local recurrence was found in 53 (36.3%) in the SH group and in 19 (31.6%) sites in the RH group, while based on KaplanMeier method no significant difference was observed in the rates of local recurrence between the SH and RH groups, p = 0.93 [8]. To date only older studies that include patients with stage IIA disease, have demonstrated superior outcomes for patients undergoing RH. Sartori et al. found a 94% OS rate for 68 patients undergoing RH compared to 79% for 135 patients undergoing simple hysterectomy [13]. Similar to our study, Cohn et al. examined the survival of 162 comprehensively staged pathological stage II patients managed in 6 academic institutions, 25% underwent radical hysterectomy with an improved disease free survival (94% vs 76%, p = 0.05) after a median follow-up of 26 months [14]. Two prior population-based studies have investigated the role of radical hysterectomy for patients with stage II endometrial cancer. Similar to our study, Wright et al. examined the Surveillance Epidemiology and End Results (SEER) database and identified 1577 patients with pathologic stage II disease [8]. Authors reported a rate of radical hysterectomy of 24% however RH had no effect on survival (HR: 0.86; 95% CI: 0.61–1.23) [10]. A limitation of that study was the inclusion of patients with endocervical gland involvement only (n = 495) currently assigned to stage I disease according to the revised endometrial cancer staging schema [8]. In another study using the SEER database, Koskas et al. performed a 2:1 matching analysis and compared the oncologic outcomes of 273 patients with type 1 endometrial cancer who underwent a radical hysterectomy for pathological stage II endometrial cancer with 546 patients who received a simple hysterectomy [9]. The 3-year cancerrelated survivals in the radical and simple hysterectomy groups were 88.7% and 94.1%, respectively. After adjusting for radiation therapy administration, there was no difference between the two groups in terms of cancer-related survival or overall survival [9]. A major strength of the present study is the large number of surgically staged patients identified. Moreover, we were able to control for multiple confounders and perform stratified analyses, as well as a sensitivity analysis that included patients with clinical stage II disease. However, several limitations should be noted. Firstly, surgical codes as provided by the NCDB were used to identify patients who had simple, modified radical and radical hysterectomy. As such we could not verify whether each individual surgeon used a classification system such as the Piver-Rutledge-Smith or Querleu-Morrow classification systems, while we could not perform quality control for each type of surgery. Given the absence of preoperative data a potential selection bias is pausible. Patients with more aggressive appearing tumors may have been more likely to undergo RH. Due to the lack of central pathology report, possible tumor misclassifications cannot be excluded. Information on patient related parameters that may have influenced surgeon choice towards RH or SH such as patient's surgical history, uterine size, and
Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003
D. Nasioudis et al. / Gynecologic Oncology xxx (xxxx) xxx
specific comorbidities, were lacking. Similarly, indications and rationale of adjuvant chemotherapy and radiotherapy administration for each patient is not collected. We could not also verify whether patients who did not undergo para-aortic LND received radiation therapy to the paraaortic lymphatic beds. In addition, the NCDB does not collect information on cancer relapse or the cause of death, precluding us from analyzing differences in progression free and cause specific survival. Lastly, contrary to major randomized trials we found a survival benefit among patients who received radiation therapy. We could not verify whether this benefit is attributed to patient selection bias since functional status is not collected in the NCDB. The results of the present study do not support the routine use of radical hysterectomy for stage II endometrial cancer. A possible future international randomized trial may clarify the surgical management for patients with stage II endometrial cancer, though technically challenging. Contributions DN: conception, statistical analysis, critical analysis, and drafting/ final editing. SS: critical analysis and drafting/final editing. EK: critical analysis and drafting/final editing. AH: critical analysis and drafting/final editing. RG: critical analysis and drafting/final editing. RB: critical analysis and drafting/final editing. MM: critical analysis and drafting, final editing. NA: supervision, critical analysis and drafting/final editing. Declaration of competing interest No conflicts of interest to report.
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Please cite this article as: D. Nasioudis, S. Sakamuri, E.M. Ko, et al., Radical hysterectomy is not associated with a survival benefit for patients with stage II endometria..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.02.003